Pembrolizumab Monotherapy Elicits Responses in Patients With Advanced Rare Cancers

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Treatment with pembrolizumab demonstrated antitumor activity along with tolerable toxicity in patients with 4 different rare and hard-to-treat malignancies, according to results from a phase II study led by The University of Texas MD Anderson Cancer Center researchers and published in the Journal for ImmunoTherapy of Cancer.

Aung Naing, MD

Aung Naing, MD

Aung Naing, MD

Treatment with pembrolizumab (Keytruda) demonstrated antitumor activity along with tolerable toxicity in patients with 4 different rare and hard-to-treat malignancies, according to results from a phase II study led by The University of Texas MD Anderson Cancer Center researchers and published in theJournal for ImmunoTherapy of Cancer.1

“Our findings that pembrolizumab has a favorable toxicity profile and anti-tumor activity in patients with these rare cancers supports further evaluation in these populations,” said lead author Aung Naing, MD, associate professor of investigational cancer therapeutics, in a statement. “Finding solutions for treatment is vital given that patients with advanced rare cancers have poor prognosis and few treatment options.”

A total of 128 patients with advanced rare cancers—including squamous cell carcinoma of the skin ([cSCC], n = 19), carcinoma of unknown primary ([CUP], n = 22), adrenocortical carcinoma ([ACC], n = 15), paraganglioma—pheochromocytoma (n = 9), small cell malignancies of non-pulmonary origin (n = 11), medullary renal cell carcinoma (n = 4), penile carcinoma (n =3), vascular sarcoma (n = 7), germ cell tumor (n = 12), and other rare tumors (n = 25)—were enrolled in the study into one of 10 cohorts. Of these patients, 127 were included in the analysis as one patient was excluded due to a change in their diagnosis.2

Seventeen patients were not evaluable for the primary end point of non-progression rate (NPR) at 27 weeks per immune-related (ir) RECIST criteria. Most patients had measurable disease, except for 4 out of 110, including 2 patients in the other-rare-cancers cohort, which allowed for patients with evaluable disease. There were 2 patients with SCC and CUP in whom investigators found measurable disease initially but later determined that the patients had evaluable disease and could be included in the analysis as non-target lesions were used to follow them in the response evaluation.

Confirmed objective responses (ORs) were observed in 15 out of 110 patients, achieving an objective response rate (ORR) of 14% (95% CI, 8%-21%). Twenty-five percent of the overall study population had stable disease (SD) for at least 4 months (n = 27), which exemplified a clinical benefit rate (CBR) of 38% (95% CI, 29%-48%). All patients with an OR remained on the study for 8 months or more (range, 8.1-23.5 months) and 73% of those patients were still on treatment at the time of the last follow-up.

Four tumor-specific cohorts achieved the best ORs in the study, which were cohort 1 (SCC of the skin), cohort 3 (ACC), cohort 5 (CUP), and cohort 9 (paraganglioma—pheochromocytoma). The ORR in cohort 1 was 31% with the best response being a complete response (CR) in 1 patient. There was also 4 partial response (PRs), and 2 patients with SD in cohort 1. In cohort 3, the ORR observed was 15% with no CRs, 2 PRs, and 6 patients with SD. Cohort 5 achieved an ORR of 23% with no CRs, 3 PRs, and 4 participants with SD. In cohort 9, the ORR was 0, with no CRs or PRs observed, but there were 6 patients with stable disease in the group. In terms of progressive disease, cohorts 1, 3, 5, and 9, had 9, 5, 6, and 2 cases, respectively.

In terms of the primary end point in the high response cohorts, the NPR at 27 weeks in cohort 1 was 36% (95% CI, 13%-65%). In cohort 3, the NPR at 27 weeks was 31% (95% CI, 9%-61%). Cohort 5 exhibited a 27-week NPR of 33% (95% CI, 10%-65%). Finally, in cohort 9, the NPR at 27 weeks was 43% (95% CI, 10%-82%).

At the time of data cutoff (July 27, 2018), 6 out of 8 patients who were evaluable for response had an irSD and 100% had disease control for more than 4 months, exhibiting a CBR of 75% (95% CI, 35%-97%). Additionally, 3 out of 6 patients were continuing treatment at 5.0, 8.5, and 19.8 months after the start of treatment. There was also 1 patient with a 56% decrease in target lesions who was considered to have progressive disease due to the presence of new non-target lesions in the liver, which was confirmed in a subsequent scan.

In the other study cohorts, some responses were observed. Specifically, 1 patient in the penile carcinoma cohort responded, as did 4 patients in the other-rare-­­cancers group.

Of the 127 patients who received at least one dose of pembrolizumab during the study, 94% encountered a treatment-emergent adverse event (TEAE). Fifty-two percent of the toxicities observed were treatment-related adverse events (TRAEs). The most common any-grade TRAEs observed in the overall population were fatigue (20%), rash/maculopapular (13%), hypothyroidism (11%), and anorexia (9%). The most common grade 3/4 TRAEs were anemia (3%), increased alanine aminotransferase (2%), and pneumonitis (2%).

In the open-label, phase II trial, pembrolizumab 200 mg was administered intravenously for 30 minutes on day 1, then repeated 21 days for up to 24 months as long as patients showed no disease progression or toxicity. Patients who achieved a clinical response or disease stabilization were allowed to continue treatment for up to an additional 12 months.

At baseline, tumor imaging was performed and repeated 9 weeks for the first 6 months of therapy and every 12 weeks thereafter at the discretion of the treating physician if patients showed CR, PR, or SD for more than 27 weeks. Additionally, investigators performed a biomarker analysis at baseline on fresh or archival tissue to score PD-L1 and tumor-infiltrating lymphocytes (TILs).

The study followed a Simon’s optimal 2-stage design for each of the 9 cohorts and planned futility interim analyses for each of the tumor-specific cohorts to assess the primary end point.

The secondary end points of the study included the safety and tolerability of pembrolizumab, ORR, CBR, and association of NPR at week 27 with baseline PD-L1 status. The study also looked at an exploratory end point, which was the potential of TILs as a predictor of therapy effectiveness.

Eligible patients included those who were18 years and older with histologically confirmed advanced rare cancers, whose disease had progressed while on standard therapies within the last 6 months. Patients were required to have measurable disease according to RECIST v1.1 or irRECIST criteria, an ECOG performance status of 0 or 1, and adequate organ and bone marrow function. The study excluded patients who were previously treated with an anti—PD-1, anti–programmed cell death ligand (PD-L1), or anti–PD-L2 agent.

“Studies such as this one are key since rare cancers collectively accounted for 13% of all new cancer diagnoses and 25% of all cancer-related deaths in adults in 2017,” said Naing.1“The 5-year survival rate is 15% to 20% lower than for more common cancers. The poor outcomes associated with rare cancers have been attributed to difficulty or delay in diagnosis, limited access to centers with expertise such as MD Anderson, and limited therapeutic options.”

Further investigation of the clinical benefit associated with pembrolizumab is warranted based on the study findings, Naing noted.


  1. Pembrolizumab shows promise for some advanced, hard-to-treat rare cancers [news release]. Houston, Texas: University of Texas MD Anderson Cancer Center; March 19, 2020. Accessed March 20, 2020.
  2. Naing A, Meric-Bernstan F, Stephen B, et al. Phase 2 study of pembrolizumab in patients with advanced rare cancers.Journal for ImmunoTherapy of Cancer.2020;8:e000347. doi: 10.1136/ jitc-2019-000347.
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